Perturbation of the T lymphocyte lineage in transgenic mice expressing a constitutive repressor of nuclear factor (NF)-kappaB.

Boothby MR, Mora AL, Scherer DC, Brockman JA, Ballard DW
J Exp Med. 1997 185 (11): 1897-907

PMID: 9166419 · PMCID: PMC2196335 · DOI:10.1084/jem.185.11.1897

Members of the nuclear factor (NF)-kappaB/Rel family transcription factors are induced during thymic selection and in mature T lymphocytes after ligation of the T cell antigen receptor (TCR). Despite these findings, disruption of individual NF-kappaB/Rel genes has revealed no intrinsic defect in the development of mature T cells, perhaps reflecting functional redundancy. To circumvent this possibility, the T cell lineage was targeted to express a trans-dominant form of IkappaBalpha that constitutively represses the activity of multiple NF-kappaB/Rel proteins. Transgenic cells expressing this inhibitor exhibit a significant proliferative defect, which is not reversed by the addition of exogenous interleukin-2. Moreover, mitogenic stimulation of splenocytes leads to increased apoptosis of transgenic T cells as compared with controls. In addition to deregulated T cell growth and survival, transgene expression impairs the development of normal T cell populations as evidenced by diminished numbers of TCRhi CD8 single-positive thymocytes. This defect was significantly amplified in the periphery and was accompanied by a decrease in CD4(+) T cells. Taken together, these in vivo findings indicate that the NF-kappaB/Rel signaling pathway contains compensatory components that are essential for the establishment of normal T cell subsets.

MeSH Terms (24)

Animals Apoptosis CD4-Positive T-Lymphocytes CD8-Positive T-Lymphocytes Cell Division Cell Lineage DNA-Binding Proteins Electrophoresis, Polyacrylamide Gel Flow Cytometry I-kappa B Proteins Immunoblotting Interleukin-2 Mice Mice, Transgenic NF-kappa B NF-KappaB Inhibitor alpha Proto-Oncogene Proteins Proto-Oncogene Proteins c-rel Receptors, Antigen, T-Cell Signal Transduction Spleen T-Lymphocyte Subsets Thymus Gland Transcription Factor RelA

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